small animal radionuclide imaging: instrumentation ... · department of radiology small animal...

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MIPS Stanford UniversityMolecular ImagingProgram at Stanford

School of MedicineDepartment of Radiology



Small Animal Radionuclide Imaging:Instrumentation, Performance, and Applications

Craig S. Levin, Ph.D.Stanford University School of Medicine

Department of Radiology



Small Animal Radionuclide Imaging

•Small Animal Positron Emission Tomography (PET)Instrumentation requirements and challengesCommercially available systemsNew approaches

•Summary

Outline of talk:



Nuclear decays of interest for imaginggenerate high energy photons

e+Gamma Ray

Annihilation Photons

Gamma decay: Nuclear de-excitation Positron decay: Nuclear transmutation

Example: 99mTc --> 99Tc + γ

Short-livedexcitednucleus

γ−ray+Stablestate ofnucleus

Example: 18F --> 18O + e+ + ν

+ e+

positron

ν+Short-livedunstablenucleus

Morestableisotope

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Small Animal PET System Design Wish List

•Reconstructed spatial resolution ≤ 1 mm•Uniformity of spatial resolution•Sensitivity (coincidence detection efficiency) > 10%•Energy resolution ≤ 12% FWHM at 511 keV•Coincidence time resolution ≤ 2 ns FWHM•Live time > 95%•Robust image reconstruction algorithm•Accurate data correction and calibration•Reasonable cost



Positron Emitter Variations inpositron trajectory-Effects on resolution

depend on isotope

Variations in annihilationphoton non-collinearity-

Effects on resolutiondepend on system diameter

Variations in photoninteraction location-

Effects on resolution dependon detector element size

Detector Gantry

e+

Limitations on PET Spatial Resolution

MolecularProbe

DetectorElement



SPAT

IAL

RESO

LUTI

ON

(mm

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0 cm10 cm20 cm80 cm

0 cm10 cm20 cm80 cm

DETECTOR ELEMENT WIDTH (mm)

SystemDiameter

FWHM FWTM

{BlurringFunctions

PositronRange

PhotonNon-collinearity

DetectorWidth

18F

Spatial Resolution Limit for 18F PET

~500µm spatial resolution (fwhm) is possible in theory

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Non-Uniform Resolution Due toPhoton Penetration in Crystals

= (Δd/2) r / [R+(Δd/2)]

= r / [(D/Δd)+1]

Upper Limit on Radial Resolution Blurring(see drawing for definition of symbols):

(an “upper” limit since Δx is calculatedassuming two isolated crystals as shown;the presence of other adjacent absorbingdetector crystals weights the calculationtowards shallower average interaction depth)

θi

RΔxupper

Δd

θi

r

crystalfinger

detectorgantry

Δrupper ≈ Δxupper/2 = (Δd/2)·sinθi (FWHM)



Δrupper ≈ r / [(D/Δd)+1]

For a mouse positioned atcenter with diameter of 3 cm,at radial position r=1.5 mm,and system depth resolutionΔd=10 mm, theradial blurring contributionΔr<1.5 mm FWHM

Δd

Non-Uniform Resolution Due toPhoton Penetration in Crystals



Challenges for High Resolution PET Detectors

Requirements for Crystal Arrays:

•Narrow (≤1 mm) for high spatial resolution•Long (20-30 mm) and tightly packed

for high coincidence detection efficiency•Need robust light signal for best coincident time resolution,

energy resolution, detection efficiency,and crystal identification; These parameters determinecontrast resolution and quantitative accuracy.

511 keV photonI. Getting light out of long,skinny crystals

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High Geometric Efficiency(Ω/4π):

Photon detectors should be asclose to the body, cover aslarge an axial FOV and be astightly-packed as possible:

Ω ≈ 4π (A/D)×P

A=axial field-of-viewD=diameterP=crystal packing fraction

High Intrinsic DetectionEfficiency (ε):

511 keV photon detectorsshould have high Z, highdensity, and be thick for highstopping power:

ε = (1-e -µx)×f

µ=attenuation coefficientx=crystal thickness/lengthf=fraction of events withinenergy window

Coincidence Detection:

ε2 = [(1-e -µx)×f]2

Sensitivity (%) ≈ 100×(Ω/4π)×ε2 = 100×(A/D)×P×[(1-e-µx)×f ]2

Photon Count Sensitivity(Coincidence Efficiency) for PET



Types of Coincidence Events

Scatter and randoms are reduced with better energy and time resolutions

Frontview

Sideview

Random

True

Scatter

Absorbedsinglephoton

Escapedsinglephoton



Scintillator EffectiveZ

Density(g/cc)

1/eattenuation

length at511 keV

(cm)

Relativelightyield

(%NaI)

Refractiveindex

Decaytime(ns)

Peakemission

wavelength(nm)

Rugged?

“BGO” Bi4(GeO4)3 75 7.13 1.06 15 2.15 300 480 Yes“LSO”

Lu2(SiO4)O:Ce 66 7.4 1.13 75 1.82 42 420 Yes

“GSO”Gd2(SiO4)O:Ce 59 6.71 1.4 20 1.85 60 440 Yes

“LYSO”Lu1.8Y0.2(SiO4)O:Ce 65 7.1 1.2 107 1.81 40 420 Yes

“Sodium Iodide”NaI(Tl) 51 3.67 2.94 100 1.85 230 410 No

Inorganic scintillation crystals for PET

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Commercially Available Small Animal PETInstrumentation

•Concorde Microsystems, Knoxville TN “microPET” [Scintillation detectors (LSO), fiber-coupled]•Oxford Positron Systems, Oxfordshire, UK “HIDAC” [MWPC Detectors (lead converters, gas)]•Philips Medical Systems, Philadelphia, PA “Mosaic” [Scintillation detectors (GSO)]•GE-Suinsa Medical Systems, Madrid, Spain “eXplore Vista” [Dual-layer scintillation detectors (LSO-GSO)]•Gamma Medica, Northridge, CA “X-PET” [Scintillation detectors (BGO) + SPECT/CT]•Advanced Molecular Imaging, Quebec Canada “LabPET” [Scintillation detectors-Avalanche Photodiodes]



Concorde Microsystems microPET Focus

Focus 120 Focus 220

Bore size 120 mm 220 mmAxial FOV 780 mm 780 mmResolution 1.3 mm 1.3 mmCoincidence Efficiency >6.5% >4.0%Energy Resolution 18% 18%Peak NEC >580kcps >700kcps

R4 & P4

Courtesy of Stefan Siegel, Concorde Microsystems

1.5x1.5x10 mm3 LSO 2.2x2.2x10 mm3 LSO

511 keV flood responseof detector block Energy spectrum in LSO

Focus

Detector cassette

Fiberoptics

PSPMT



microPET Focus Performance

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Image Resolution

Focus TangentialFocus RadialFocus Axial

R4 TangentialR4 RadialR4 Axial

mm

Radial Offset (mm)

•250-750 keV energy window

•10 ns timing window

•Fourier rebinning, 2D FBP

FWH

M (

mm

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Reconstructed point source resolution

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Activity (mCi)

NE

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250-750 keV 10 ns250-750 keV 6 ns350-650 keV 10 ns350-650 keV 6 ns

Count rate performance(mouse phantom)

T2

T+S+2RNEC =

T= “true” coincident rateS= scatter coincident rateR= random coincident rate

Courtesy of Yuan-Chuan Tai, Washington University

Concorde P4, FBP Concorde Focus, FBP

Fourier rebinning + 2D FBP /Ramp filter.1.2 mm

1.6 mm

2.4 mm 3.2 mm

4.0 mm

4.8 mm

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microPET Focus Images

end-systole end-diastole non-gated

Courtesy of Douglas Rowland, Washington University

362.6 g S.D. Rat0.966 mCi 18FDG1.8 hr P.I. 30 min scan~23 ms frames

Cardiac Gated Images (Rat) Neuro-receptor imaging(mouse)

20 g mouse injected with 11C-CFT



GE-Suinsa eXplore Vista (Argus)

· Ring diameter: 11.8 cm· Aperture: 8 cm· Effective transverse field-of-view: 6 cm· Axial FOV: drT: 4.6 cm (srT = 2.0 cm)· Number of depth-of-interaction detector modules: 36 (18) PS- PMTs· Number of dual-scintillator depth-of-interaction elements: 6,084 (3,042)· Depth identification method: pulse shapediscrimination· Crystal array pitch: 1.55 mm· Total number of crystals: 12,168 (6,084)· 3D (coincidences and singles)· Total number of coincidence lines: 28.8 M (7.2M)

Detector module 511 keV field flood

crystal pitch = 1.55 mm

Spatial resolution in central slice:1.45 mm radial1.56 mm tangential1.74 mm axial3.9 mm3 Volume resolutionCoincidence timing resolution:1.5 ns FWHMCentral point source sensitivity:4.0% [250-700 keV]5.7% [100-700 keV]Peak NEC rate with mouse phantom:185,000 cps [250-700keV] @ 15 µCi/cc

Courtesy of Juan José Vaquero, Universitario Gregorio Marañón

Dual-layer LYSO-GSO detectors



µDerenzo Phantom3D FORE/2D FBP

1.6 mm

4.8 mm

4.0 mm

3.2 mm2.4 mm

1.2 mm

transverse sagittal coronal

cortex cortex

spinal cord

cortex

Awake Rat (F-18 FDG)

ARGUS 3D OSEM reconstruction with resolution recovery

GE-Suinsa eXplore Vista (Argus)

Courtesy of Juan José Vaquero, Universitario Gregorio Marañón

Imaging performance

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Brookhaven National Laboratory, USAClear PET Collaboration, Multi-nationalHamamatsu University, JapanHammersmith Medical Center, UKHarvard University, USAIndiana University, USAKing’s College UKMontreal Neurological Institute, CanadaNational Institutes for Health, USAStanford University, USAUniversitario Gregorio MarañónUniversity of California, Davis, USAUniversity of California, Los Angeles, USAUniversity of Julich, GermanyUniversity of Munich, GermanyUniversity of Pennsylvania, USAUniversity of Pisa, ItalyUniversity of Sherbrooke, CanadaUniversity of Texas, USAUniversity of Southwestern Texas, USAUniversity of Washington, USAWashington University, USA

Research Institutions Developing SmallAnimal PET Instrumentation



New Technologies for Small AnimalPET System Design

•Improved Scintillation Detectors•Semiconductor Detectors



•Narrow (≤1 mm) for high spatial resolution

•Long (20-30 mm) and tightly packed for

high coincidence detection efficiency

and…don’t forget...

•Need high light extraction with low variation for best time resolution,

energy resolution, detection efficiency, and crystal identification;

these parameters will help to optimize contrast resolution andquantitative accuracy by helping to reject background events.

511 keV photon

Is it possible to build a high performance PETsystem with 1 mm crystal pixels?

Requirements for Crystal Arrays:

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How can we collect >90% of light from tinyarray crystals?

++

+

+

+

+

+

+

+

++

+

+

+

+

++

+

+

Instead ofcollecting thelight from thesmall end

(a small fraction of lightis collected)

Collect thelight fromthe long side

(a high fraction oflight is collected)

Light CollectionEfficiency:

f ∝ (A/L)(1 - 1/n2)

A

L

n = refractive index



Light Collection Improvements (1x1 mm2 pixels)

0102030405060708090100

0102030405060708090100

LSO BGO GSO

GROUND SURFACEWHITE REFLECTOR

POLISHED SURFACEWHITE REFLECTOR

1x1x10 mm 3

0102030405060708090100

0102030405060708090100

LSO BGO GSO

1x1x20 mm 3

GROUND SURFACEWHITE REFLECTOR

POLISHED SURFACEWHITE REFLECTOR

6 mm long 20 mm long10 mm long

For proposed scheme•Nearly all available scintillation light is collected (≥95%)•Light collection efficiency is independent of crystal length,width and surface treatment•Light collection efficiency is independent of the light origin•Results in superior energy and time resolution



How could we collect more light from arrays ofminiscule (1 mm) crystals?

Instead of this...

Can we do this?

Photodetectorat crystal

ends

Thin photodetectors at crystal

sides

PSPMT

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Scintillation detector arrays with “edge-on” position sensitive avalanchephotodiode (PSAPD) arrays between crystal planes

511 keVphoton

511 keVphoton•~2 cm thick of LSO

detectors in two stackedblock modules

•Each modulecomprises 8 layers

•Each layer comprises3x8 arrays of 1x1x3mm3 LSO crystals (left)or 1 mm thick sheets(right)

•This gives ~ 1-3 mminteraction depthresolution

•Thin PSAPDs required

2 cmthick

9x9x1 mm3

LSO sheets

1x1x3 mm3

LSO crystals

Need: extremely thin PSAPD

New Approach for PET Detector Design



•Made by RMD, Inc.•8x8 mm2 area•Gain ~1000•Leakage Current ~1-2 µA•Capacitance ~0.7 pf/mm2

~45 pf•Noise ~130 e- rms

Two sizes: 8 mm or 13 mm

(A+B)-(C+D)X =A+B+C+D

A

B

C

D

(X,Y)

Problem: Standard PSAPD is not thin enough for high crystal packing fraction in ourproposed detector design

ScintillationLight flash

Cornercontacts

(A+C)-(B+D)Y =A+B+C+D

Selected Scintillation Light SensorPosition sensitive avalanche photodiode (PSAPD)



Standard chip andceramic package

Thin chip and Kaptonpackage (~230 micron thick)

Flex circuitaccomodates twothin PSAPD chipson a same plane

Standard vs. Thin PSAPD

New Light Detector:Position Sensitive Avalanche Photodiode (PSAPD)

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Novel “edge-on” detector configuration usingposition sensitive avalanche photodiodes

One layer of detector modulecomprising PSAPD coupled to a 3x8array of 1X1X3-mm3 LSO crystals.Half ground and half polished crystalswere used to compare spatial, energyand temporal resolution performance.

1.0 mm intra-layercrystal pitch

511 keVphotons

10 mm of LSO 1x1x3mm3

LSO crystals

PSAPD + flexcircuit + reflector

(<300 µm totalthickness)

Flex circuit forsignal readoutand HV bias

1.3mm interlayercrystal pitch

2.2 cm

Novel, ultra-thin (<300 µm) position-sensitive avalanchephotodiodes (PSAPD) are placed between the crystallayers with incident 511-keV photons entering parallel tothe PSAPD plane (“edge-on”) as shown. This designgives direct measurement of photon depth-of-interactionand an effective 2-cm thickness of LSO crystal.

Groundcrystals

Polishedcrystals

Second PSAPD chiplocation (not mounted)

PSAPD chip

Flex circuit

Electricaltraces



jin new123x81x1x3fldr30.l

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Flood irradiation of 8x3 array of 1x1x3 mm3 crystalsside coupled to thin PSAPD

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No intercrystal reflectors

Flood histogramProfile through center

15:1 peak:valley ratio

Excellent crystal identification due to high light collection efficiency

No intercrystal reflectors



Spatial resolution of LSO-PSAPD detector layers

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22NaLSO PMT

PSAPD

LSOarray

Scan direction

FWHM of the point spread functionsis measured to be about 1.0 mm.Left figure shows the top view ofexperimental setup used to measurecoincidence time resolution and pointspread function by edge-on scanning.

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Ground crystals Polished crystals

Thin PSAPD: energy spectra of individual crystals3x8 array of 1x1x3 mm3 LSO crystals



Measured energy and time resolutions ofLSO-PSAPD modules

Experimental measurements show that the average energy resolution is 11.0±1%,coincidence time resolution is 2.1±0.1 ns.

Coincidence time spectrum

Coun

ts

40 45 50 55 60 65 700

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Time difference (ns)

← FWHM: 2.1 ns

TAC Data

Gaussian FitPSAPD START,

PMT STOP

9.91%FWHM at 511 keV

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Voltage (v)

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22Na Energy Spectrum



Energy resolution comparison conventional vs. proposed high res PET

Proposed PET system:LSO-PSAPD

Conventional µPET system:LSO-Fiber-PSPMT

These proposed energy resolution improvements will yieldenhanced sensitivity, image contrast and quantitative accuracy

10.4%fwhm

at 511 keV

26.1%fwhm

at 511 keV

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Summary Great progress has been made in pre-clinical radionuclide imaginginstrumentation

PET:•There are now six vendors for high resolution PET systems for smallanimal imaging•Over twenty research groups working on high resolution PET systemsworld wide•Sensitivity and spatial resolution, and energy resolution all continue toimprove•Efforts to fuse this information onto high resolution CT and MR are beingmade

In order for small animal imaging to assist existing drug development andtesting protocols, must push for highly accurate image data and means toextract quantitative information that accurately characterize molecularsignals

small animal radionuclide imaging: instrumentation ... · department of radiology small animal...

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